Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis

Abstract

Tight coordination of cell proliferation and differentiation is central to red blood cell formation. Erythropoietin controls the proliferation and survival of red blood cell precursors, while variations in GATA-1/FOG-1 complex composition and concentrations drive their maturation. However, clear evidence of cross-talk between molecular pathways is lacking. Here, we show that erythropoietin activates AKT, which phosphorylates GATA-1 at Ser310, thereby increasing GATA-1 affinity for FOG-1. In turn, FOG-1 displaces pRb/E2F-2 from GATA-1, ultimately releasing free, proproliferative E2F-2. Mice bearing a Gata-1S310A mutation suffer from fatal anemia when a compensatory pathway for E2F-2 production involving insulin-like growth factor-1 (IGF-1) signaling is simultaneously abolished. In the context of the GATA-1V205G mutation resulting in lethal anemia, we show that the Ser310 cannot be phosphorylated and that constitutive phosphorylation at this position restores partial erythroid differentiation. This study sheds light on the GATA-1 pathways that synchronize cell proliferation and differentiation for tissue homeostasis.

Tipping the balance between erythroid cell differentiation and induction of anemia in response to the inflammatory pathology associated with chronic trypanosome infections

“…This finding corresponds to the size increase of the erythroid population during infection, annotated by the specific gene markers Gypa , Hbb-bt , and Tfrc ( Figures 4D, E ). Finally, it is worth mentioning that EBIM and TRM2 are increased for the gene encoding Insulin-like growth factor 1 ( Igf1 ) ( Figure 4C ), which has been reported to be produced by macrophages to promote erythroid cells proliferation ( 59 ). Hence, combined evidences indicates that T. evansi -induced TRMs and EBIMs all play a central role in infection-induced extramedullary erythropoiesis.…”

An R307H substitution in GATA1 that prevents Ser310 phosphorylation causes severe fetal anemia

“…Mice harboring a Gata1 S310A mutation develop severe anemia when a compensatory pathway for EF-2 production (IGF1 signaling) is abolished. 21 Furthermore, our patient developed severe fetal anemia and manifested with persistent anisocytosis and elevated levels of HbF during childhood (39.7% HbF at birth; 6.7% at 5 years of age). Previous studies have shown that GATA1 plays a fundamental role in fetal globin gene expression (eg, gene silencing of HBG1 and HBG2 and hemoglobin switching to HBB is promoted by GATA1).…”

“…The role of Ser310 phosphorylation for GATA1 affinity to FOG1 is historically controversial, depending on the experimental setup used. 21-24 Nevertheless, the clinical presentation of our patient with severe fetal anemia and thrombocytopenia and impaired maturation of the erythrocytes, combined with reduced phosphorylation resulting in impaired GATA1/FOG1 binding in R307H mutation, underlines the clinical relevance. Kadri et al showed that phosphorylation at Ser310 enhances the affinity of GATA1 for its cofactor, FOG1.…”

“… 7 , 15-17 Electrophoretic mobility shift assay (EMSA) showed that DNA binding of GATA1 R307H was strongly reduced in hemin-stimulated K562 cells ( Figure 2A ) and comparable in Jurkat cells (supplemental Figure 1A), indicating that the R307H mutation inhibits DNA binding of GATA1 in erythroid cells. Given that other mutations (eg, V205M, G208S, and D218G) 6 , 11-13 are known to reduce the affinity of GATA1 for FOG1 and that preclinical data have demonstrated murine Ser310 to be essential for erythroid differentiation, 21 we determined the phosphorylation status on Ser310. No phosphorylation of GATA1 R307H on Ser310 in K562 and Jurkat cells was observed in western blot analysis ( Figure 2B ; supplemental Figure 1B).…”

Renal Klotho and inorganic phosphate are extrinsic factors that antagonistically regulate hematopoietic stem cell maintenance

“…Moreover, scRNA-seq revealed that the expression levels of GATA2 and its coactivator friend of GATA-1 (FOG1) were relatively higher in Mk-HSCs (Figure 6B). GATA factors can be phosphorylated by Akt to increase its affinity for FOG1 (Kadri et al, 2015). GATA2 phosphorylation at Ser401 (Figure 6C) and GATA2/FOG1 association (Figure 6D) were enhanced (C and D) Frequency and CD41 expression of HSCs after 14-day culture in CM (0.9 mM Pi) and HPM (4 mM Pi) with or without soluble Klotho supplementation (n = 5).…”